Chapter 8 Endocrine physiology

Endocrine regulation is an important element of homeostatic control. Integration of endocrine and nervous controls is a major function of the hypothalamus. These neuroendocrine links will be considered in some detail, along with the actions of various hormones which regulate cell metabolism or some aspects of fluid and electrolyte balance. Other functions which are also under endocrine control are considered elsewhere, e.g., cardiovascular performance (Ch. 3), renal function (Ch. 5), gastrointestinal motility and secretion (Ch. 6) and reproductive physiology (Ch. 9).

8.1 Principles of endocrine function

Learning objectives

At the end of this section you should be able to:

• describe the main features of hormonal control

• outline how hormone release is controlled.

Endocrine control involves secretion of a hormone into the circulation. This messenger molecule binds to any cells which carry the relevant receptors, initiating the observed response (Section 1.5). As far as the target cell is concerned this is similar to other forms of chemical signalling, e.g., chemical neurotransmission. Indeed, a given substance may act both as a neurotransmitter and as a hormone at different sites. For example, noradrenaline (norepinephrine) is a postganglionic sympathetic neurotransmitter but is also released into the circulation as a hormone from the adrenal medulla (Section 7.6). Because of the large diffusion distances and circulation delays involved, however, hormonal responses are generally slower in onset than those mediated by nerves. They are also more persistent, since removal of the hormone from the bloodstream may take some time after secretion has stopped.

The release of endocrine substances is controlled in three ways:

8.2 Hypothalamic and pituitary function

The hypothalamus regulates both autonomic nervous activity (Section 7.7) and several aspects of endocrine function. The latter role is fulfilled through its links with the pituitary gland, which secretes a wide range of hormones. Some of these regulate human physiology directly, while others control the activity of various endocrine glands around the body. The result is a multitiered endocrine control system which can be influenced through the nervous inputs to the hypothalamus.

Relevant structure

The hypothalamus is located adjacent to the third ventricle in the forebrain and is connected by the hypophyseal stalk to the pituitary gland (hypo-physis cerebri) immediately inferior to it (Fig. 159). This has two embryologically distinct components.

• The anterior pituitary, or adenohypophysis, is a classical endocrine gland containing secretory epithelial cells. It is derived from an outpouching of the developing pharyngeal epithelium (Rathke’s pouch). The anterior pituitary receives its blood supply from a series of hypophyseal portal vessels linking it with the hypothalamus.

• The posterior pituitary, or neurohypophysis, develops as a downgrowth from the brain and is continuous with the hypothalamus itself. It is made up of adapted axons which release hormones into the blood from their terminals. The cell bodies of these specialized neurones lie within the paraventricular and supraoptic nuclei of the hypothalamus.

Fig. 159 The links between the hypothalamus and the pituitary gland.

Hypothalamic control of pituitary function

This is different for the anterior and posterior lobes of the pituitary.

Anterior pituitary

The endocrine activity of the anterior pituitary is regulated by hormones secreted from the hypothalamus and transported in the hypophyseal portal blood. Each of these factors selectively promotes or inhibits the secretion of a specific pituitary hormone and so they are referred to as releasing or inhibiting hormones, respectively. They are generally oligopeptides, although prolactin-inhibiting hormone is probably the transmitter substance dopamine. Hypothalamic secretion of these pituitary-regulating hormones is influenced by neurological inputs and feedback control. Both the pituitary hormones themselves and circulating products of the endocrine systems controlled by those hormones can regulate hypothalamic secretion, usually through feedback inhibition (Fig. 160).

Fig. 160 Summary of the hypothalamic–pituitary control system. Note that secretion of both anterior pituitary and hypothalamic hormones may be inhibited by the circulating hormones whose release they stimulate. This provides negative feedback regulation of hormone levels.

Posterior pituitary

The posterior pituitary secretes two peptides which are manufactured in the cell bodies of hypothalamic neurones (Fig. 159). These hormones are packaged in vesicles and transported along the axons into the posterior pituitary itself to be stored in the axon terminals. Appropriate sensory stimuli lead to activation of the hypothalamic cells and the release of the hormones from the posterior pituitary into the bloodstream. This adaptation of neurotransmission to fulfil an endocrine role is sometimes called neurocrine control.

Anterior pituitary hormones

The anterior pituitary secretes six peptide hormones with well-defined functions in humans. These include hormones controlling the endocrine functions of the adrenal cortex, the thyroid and the gonads, as well as prolactin and growth hormone.

Adrenocorticotrophic hormone (ACTH) is secreted in response to corticotrophin-releasing hormone (CRH) from the hypothalamus. It stimulates the release of glucocorticoids from the adrenal cortex. A number of other peptides are synthesized and secreted from the anterior pituitary along with ACTH. These include the endogenous opiate β-endorphin, and precursors of melanocyte-stimulating hormone. Their roles are unclear.

Thyroid-stimulating hormone (TSH), or thyrotrophin, is secreted in response to thyrotrophin-releasing hormone (TRH) from the hypothalamus. It stimulates thyroid hormone secretion.

Follicle-stimulating hormone (FSH) and lutein-izing hormone (LH) are secreted in response to gonadotrophin-releasing hormone (GnRH) from the hypothalamus. These gonadotrophins stimulate the male and female gonads (Sections 9.2 and 9.4).

Prolactin secretion may be influenced by a prolactin-releasing hormone (PRH) but is mainly controlled by a prolactin-inhibiting hormone (PIH), (this is probably dopamine). Stimuli which reduce PIH release from the hypothalamus raise prolactin levels. This occurs during pregnancy, favouring development of the breasts ready for lactation, and as part of the suckling reflex during breast feeding. The resultant prolactin peaks stimulate milk production (Section 9.5). Prolactin also inhibits GnRH secretion from the hypothalamus, thus inhibiting the reproductive cycle during lactation.

Human growth hormone (hGH), or somatotrophin, is controlled by two antagonistic hypothalamic hormones. Growth hormone-releasing hormone (GHRH) is believed to be more important than the growth hormone-inhibiting hormone (GHIH), which is also known as somatostatin. Growth hormone is a major anabolic hormone which stimulates cell division and growth in both bony and soft tissues around the body. These effects are probably indirect, being mediated by growth promoters, known as somatomedins, produced by the liver in response to hGH stimulation. Growth hormone is particularly important during childhood and adolescence, but although it can no longer stimulate long bone growth after the epiphyses have fused, hGH continues to have important metabolic functions throughout life. These favour protein synthesis in most body tissues, while promoting the breakdown of fat for energy use. This has a carbohydrate-sparing effect, so that glycogen stores increase and blood glucose levels tend to rise. Low blood glucose stimulates hypothalamic GHRH and inhibits secretion of somatostatin, both from the hypothalamus and the δ cells of the pancreatic islets. The resulting increase in hGH helps raise glucose concentrations back towards normal. Growth hormone secretion is also stimulated by trauma and stress, through neural control of the hypothalamus.

Posterior pituitary hormones

The posterior lobe of the pituitary secretes two short chain peptide hormones, oxytocin and antidiuretic hormone.

Oxytocin is produced by cells in the paraventricular and supraoptic nuclei of the hypothalamus. These are reflexly activated by sensory inputs from mechanoreceptors in the breast during suckling, and oxytocin is released from the posterior pituitary in response. This stimulates the ejection of milk through contraction of the myoepithelial cells surrounding the milk ducts (Section 9.5). Oxytocin also stimulates uterine contraction during labour (Section 9.5).

Antidiuretic hormone (ADH) is also produced in the paraventricular and supraoptic nuclei of the hypothalamus. Sensory inputs, both from local osmoreceptors and from stretch receptors in the cardiovascular system (the cardiopulmonary and systemic arterial baroreceptors), stimulate these cells whenever the osmolality of the extracellular fluid rises, or if blood volume or blood pressure falls. The resulting increase in ADH promotes water reabsorption from the collecting ducts and distal convoluted tubules of the kidney (Section 5.4), and so tends to reduce the osmolality and expand the volume of the extracellular fluids by promoting the production of a small volume of concentrated urine. At the same time, peripheral resistance is increased through arteriolar constriction, which also helps to maintain arterial pressure (Section 3.6). This pressor effect, though less important physiologically, explains the derivation of ADH’s alternative name, which is vasopressin.

8.3 Thyroid function

The thyroid hormones are key metabolic regulators and are particularly important in determining metabolic rate and heat production.

Relevant structure

The thyroid gland is located in the neck, in front of and just below the level of the larynx, and consists of two lobes joined by a central isthmus. Histologically, it consists of numerous spherical follicles, each with an outer layer of cuboidal epithelium and filled with proteinaceous colloid (Fig. 161A). These follicles represent the functional subunits of the gland, responsible for synthesis, storage and release of the thyroid hormones. The thyroid also contains parafollicular C cells, which secrete calcitonin. These will be considered along with other aspects of body calcium regulation (Section 8.4).

Fig. 161 (A) Thyroid follicles. (B) Main steps in thyroid hormone synthesis. Iodination of tyrosine produces monoiodotyrosine (MIT) and diiodotyrosine (DIT). These are then combined to form triiodothyronine (T₃) and thyroxine (T₄).

Box 34 Clinical note: Abnormal pituitary function

This may be classified into problems arising from deficient pituitary secretion and those caused by excess hormone.

Deficient secretion

Deficiencies resulting from insults to the entire gland, e.g., because of a local tumour or its surgical treatment, may involve all the pituitary hormones, a condition known as panhypopituitarism. Alternatively, there may be a deficit in a single hormone caused by a defect in the relevant pituitary cells or in the hypothalamic cells which regulate their function. The main problems which can result are:

• corticosteroid deficiency caused by lack of ACTH (Section 8.5)

• thyroid deficiency caused by lack of TSH

• failure of sexual function caused by lack of FSH/LH

• dwarfism caused by lack of hGH in childhood; this may arise as a congenital defect and can be treated with hGH supplements

• diabetes insipidus caused by lack of ADH; this results in an inability to concentrate urine and so the patient passes 8–10 L of dilute urine per day and has to drink a commensurate volume.

Excess secretion

The following conditions resulting from oversecretion of a single pituitary hormone are observed in clinical practice:

• corticosteroid excess caused by elevated ACTH (Section 8.5)

• impaired reproductive function caused by elevated prolactin. Hyperprolactinaemia is now recognized as an important cause of menstrual failure and infertility. This seems to be caused by prolactin’s ability to block GnRH production by the hypothalamus

• abnormal growth caused by elevated hGH. This stimulates long bone growth in children, causing gigantism. If hGH levels become raised in adult life, after epiphyseal fusion, there is no increase in height, but soft tissue and body organ growth are stimulated. This is known as acromegaly. A persistent excess of hGH may eventually lead to elevated blood glucose levels, i.e., diabetes mellitus results.

• fluid retention and low plasma osmolality caused by elevated ADH. This is particularly associated with cancer of the lung and is known as inappropriate ADH secretion.

Hormone synthesis

The first step in the synthesis of the thyroid hormones involves active pumping of iodide ions (I⁻) from the extracellular space into the follicular epithelium (Fig. 161B). The trapped I⁻ enters the colloid and is oxidized to iodine, which then combines with tyrosine molecules attached to a colloid-binding protein known as thyroglobulin. Monoiodotyrosine (MIT) and diiodotyrosine (DIT) are generated as a result. These then combine to produce the hormonal products, triiodothyronine (1 MIT + 1 DIT) and thyroxine (2 × DIT). These thyroid hormones may be stored in the colloid for some months but are eventually detached from the thyroglobulin and released into the bloodstream. The quantity of thyroxine (T₄) produced greatly exceeds that of triiodothyronine (T₃), but the latter is more biologically active.

Regulation of thyroid secretion

Thyroid activity is controlled by the hypothalamus and anterior pituitary and provides a classical example of the feedback loops typical of such regulation (Section 8.2; Fig. 160). The hypothalamus releases thyrotrophin-releasing hormone (TRH) into the hypophyseal portal blood and this stimulates secretion of thyroid-stimulating hormone (TSH) from the anterior pituitary. Thyroid hormone synthesis and secretion are both stimulated by TSH. Normal levels of circulating T₃ and T₄ are maintained through their negative feedback effects on TRH and TSH secretion. Other stimuli may also influence secretion, e.g., cold conditions may stimulate hypothalamic TRH release as part of temperature homeostasis (Section 1.1).

Protein transport of thyroid hormones

Most of the thyroid hormone in the blood is bound to plasma proteins, particularly thyroid-binding globulin (TBG). This transport is necessary as T₃ and T₄ are lipophilic molecules which would not dissolve readily in the aqueous plasma. Protein bound hormone also provides a reservoir which helps to maintain steady tissue levels. Only free (unbound) hormone is biologically active, however, since only it can diffuse out of the capillaries and into body cells. Increasing the concentration of plasma binding proteins may increase the total concentrations of T₃ and T₄ without affecting the levels of free hormone and this may have to be considered when interpreting hormone assays, e.g., the normal values for total T₄ concentrations in plasma increase during pregnancy as a result of increased protein binding, but this is not associated with a rise in the concentration of free hormone.

Intracellular actions of thyroid hormones

Because they are lipid-soluble, both T₃ and T₄ can diffuse across the plasma membrane and act intracellularly. A large proportion of the T₄ is converted to T₃ within the target cell and thyroid hormone receptors on the nucleus bind T₃ with a higher affinity than T₄. Receptor binding stimulates increased DNA transcription and, therefore, promotes protein synthesis. This leads to increased enzyme activity, elevating metabolic rate and promoting growth.

Whole body actions of thyroid hormones

These are many and varied but may be summarized briefly under the headings of metabolic, systemic and developmental effects.

Box 35 Clinical note: Abnormal thyroid function

This leads to inadequate or excess amounts of circulating thyroid hormone.

Deficient secretion

Inadequate thyroid secretion is known as hypothyroidism. This may be subdivided into primary hypothyroidism and hypothyroidism secondary to deficient TSH secretion.

In primary hypothyroidism the fault lies within the thyroid gland itself. Causes include iodide deficiency, congenital thyroid enzyme deficiencies and inflammation of the gland (thyroiditis). The low T₃ and T₄ levels lead to elevated TSH levels (reduced negative feedback) and this stimulates enlargement of the thyroid, i.e., goitre formation.

In secondary hypothyroidism there is deficient TSH secretion from the anterior pituitary. This leads to thyroid atrophy rather than goitre.

The major symptoms and signs of hypothyroidism can be related to the normal metabolic, systemic and developmental actions of the hormone.

• Metabolic consequences:

– a reduced basal metabolic rate leading to cold intolerance with constricted peripheries under fairly normal temperature conditions; appetite is reduced but weight increases

– reduced blood sugar levels

– elevated blood lipids, which may eventually lead to atherosclerosis

• Systemic consequences:

– low resting heart rate

– decreased gut motility leading to constipation

– slowed thinking and somnolence; muscle stretch reflexes may be delayed

• Developmental consequences: the most important developmental consequence is irreversible mental retardation in cases of congenital hypo-thyroidism resulting from inadequate brain development in the early months of life. This condition, known as cretinism, can be prevented by screening newborn children and providing immediate thyroid replacement therapy for those who require it.

Excess secretion

Hyperthyroidism, or thyrotoxicosis, can arise in two main ways.

• Abnormal autoantibodies may bind to the TSH receptors in the thyroid and thereby stimulate the gland, which enlarges, producing a goitre, and secretes excessive amounts of T₃ and T₄. Increased negative feedback reduces the circulating levels of TSH.

• A hormone-secreting tumour (an adenoma) may develop within the thyroid. This functions independently of TSH control and so the normal regulatory mechanism is lost. TSH levels will be low so that areas of normal gland tissue will atrophy.

The major symptoms and signs of hyperthyroidism may again be summarized using the metabolic, systemic, developmental headings.

• Metabolic consequences:

– a dramatic elevation of basal metabolic rate with increased heat production, heat intolerance, vasodilatation and sweating; appetite increases but weight declines.

• Systemic consequences:

– rapid heart rates and arrhythmias, especially atrial fibrillation; the pulse is bounding, because of the large pulse pressure; persistent elevation of the cardiac output in response to the increased metabolic needs of the body may eventually lead to high-output cardiac failure

– abnormal breathlessness during exercise

– increased gut motility leading to diarrhoea

– mental overactivity and insomnia; muscle reflexes are brisk but the muscles are often weak; sympathetic nervous system symptoms include anxiety and muscle tremor

• Developmental consequences: the main result of excess thyroid secretion in childhood is early closure of the epiphyseal plates in long bones so that, although early growth may be accelerated, adult stature is reduced.

• Systemic effects:

– direct stimulation of heart rate and an indirect reduction of peripheral resistance caused by the increased metabolic demands of the tissues; cardiac output and pulse pressure tend to rise, but mean arterial pressure is little affected

– increased ventilation

– increased gastrointestinal motility and secretion

– increased CNS activity and alertness

• Developmental effects:

– stimulation of skeletal growth in childhood

– promotion of normal brain development in the early postnatal period.

8.4 Hormonal control of Ca²⁺

Calcium enters the body by absorption of dietary Ca²⁺ from the gut and is lost mainly through urinary excretion. Within the body itself, Ca²⁺ is found in a number of functionally distinct reservoirs, or ‘pools’. A variety of hormones act to regulate Ca²⁺ levels by controlling both the exchange between these Ca²⁺ pools and the rate of absorption and excretion of Ca²⁺ from the body.

Calcium pools in the body

There are three main body calcium pools (Fig. 162):

• bony skeleton

• intracellular pool

• extracellular pool.

Fig. 162 The main Ca²⁺ pools in the body. ECF, extracellular fluid.

Bony skeleton

About 1 kg of Ca²⁺ is deposited in the mineral component of the bony skeleton. Calcium phosphate crystals form within the connective tissue framework (osteoid) laid down by osteoblasts. This bone mineral provides impressive resistance to compressive loads. Resorption of bone by osteoclasts breaks down the bony matrix, releasing Ca²⁺ and phosphate back into the extracellular fluid. Bone also contains osteocytes, which can transfer Ca²⁺ to the extracellular fluid without destroying the bone structure. This provides a rapidly exchangeable pool of bone Ca²⁺ which acts as a functionally distinct fraction of total bone Ca²⁺.

Intracellular pool

The size of the intracellular Ca²⁺ pool is hard to estimate since much of it is normally bound to proteins within stores of unknown capacity. It is clear, however, that changes in cytoplasmic [Ca²⁺], whether caused by release of stores, as in skeletal muscle (Section 1.6), or by entry of Ca²⁺ from the extracellular fluid, as at the axon terminal (Section 7.2), act as important intracellular signals in controlling a wide variety of cell functions.

Extracellular pool

Calcium in the extracellular fluid is involved in continuous exchange with that in bone and body cells (Fig. 162). Absorption from the gut and urinary excretion also occur directly into and out of the extracellular space. All these processes are affected by the extracellular [Ca²⁺]. Even more importantly, extracellular Ca²⁺ is crucial in determining the ease with which excitable cells can be stimulated and so plasma [Ca²⁺] must be closely regulated. The normal value is about 2.5 mmol L⁻¹ but approximately half of this is bound to protein. The remainder consists of Ca²⁺ free in solution, and it is only this fraction which is biologically active.

Physiological functions of extracellular Ca²⁺

Several vital processes are dependent on the maintenance of an appropriate Ca²⁺ concentration in the extracellular space.

The excitability of nerve and muscle is increased by a fall in plasma [Ca²⁺] (hypocalcaemia). This may result in spontaneous skeletal muscle contraction (which can be fatal because of laryngeal spasm and respiratory arrest), cardiac arrhythmias and abnormal sensations caused by spontaneous sensory nerve activity (paraesthesia). The mechanism underlying these effects is an increase in ion channel permeability to Na⁺ in the presence of low extracellular [Ca²⁺]. This promotes inward Na⁺ currents so that the membrane depolarizes towards the threshold for action potential production. Conversely, a high extracellular [Ca²⁺] depresses nerve and muscle activity by reducing the Na⁺ current (Section 1.4).

Excitation–contraction coupling in muscle depends on an increase in intracellular [Ca²⁺] (Section 1.6). Smaller decreases in extracellular [Ca²⁺] than those which stimulate spontaneous excitability may reduce the strength of contraction, both by decreasing the influx of Ca²⁺ during the action potential and by depleting the intracellular stores within the sarcoplasmic reticulum.

Stimulus–secretion coupling refers to mechanisms leading to release of cell products following stimulation of nerve terminals and both endocrine and exocrine glands. These secretory processes are often triggered by an increase in intracellular [Ca²⁺], either due to release of intracellular stores or Ca²⁺ entry from outside the cell.

Blood clotting is dependent on plasma Ca²⁺, which acts as an essential clotting factor (Section 2.6).

Regulation of body Ca²⁺

Calcium control mechanisms act to regulate two main variables, the free [Ca²⁺] in extracellular fluid (in the short term), and the total body Ca²⁺ content (in the medium to long term). Assuming that the dietary intake is adequate, regulation of plasma [Ca²⁺] mainly depends on two hormones, parathormone and vitamin D, with a less important contribution from a third, calcitonin.

Parathormone (PTH)

This is a protein hormone secreted from four parathyroid glands located posterior to the lobes of the thyroid gland in the neck. It is responsible for the tight control of free [Ca²⁺] in the extracellular fluid and is essential for life. Parathormone secretion is directly stimulated by a fall in plasma [Ca²⁺] and acts to elevate [Ca²⁺] in several ways, thereby providing negative feedback control. It has four main actions: one in bone and three in the kidney.

• Stimulation of Ca²⁺ release from bone. Initially osteocytes mobilize Ca²⁺ from the rapidly exchangeable bone pool, transferring it into the extracellular fluid and thus raising plasma [Ca²⁺]. In the longer term, parathormone promotes a continued but slower release of bone Ca²⁺ from the osteoclastic breakdown of the bone matrix itself.

• Stimulation of the rate of Ca²⁺ reabsorption from the renal tubules so that less is lost in the urine. This helps conserve plasma Ca²⁺.

• Stimulation of urinary phosphate excretion, which reduces plasma phosphate concentration. This is important for Ca²⁺ regulation since it reduces the tendency for Ca²⁺ and phosphate ions to react, forming a solid precipitate of calcium phosphate.

• Stimulation of the rate at which vitamin D is converted to its most biologically active form, calcitriol (also known as 1,25-dihydroxycholecalciferol) within the kidney. Thus, parathormone indirectly stimulates the uptake of both calcium and phosphate from the gut by promoting the actions of vitamin D.

Vitamin D

Vitamin D is a fat-soluble vitamin which comes from two main sources, the diet (vitamin D₂ or ergocalciferol) and the skin (vitamin D₃ or cholecalciferol). These two forms differ slightly in structure but fulfil identical functions. The main dietary sources are fish, liver and ultraviolet (UV) irradiated milk, and D₂ is absorbed along with lipid in the small intestine. Alternatively, UV radiation from sunlight can convert a cholesterol derivative into vitamin D₃ in the skin. The relative importance of these sources in a given individual largely depends on the local climate.

Once in the circulation, cholecalciferol (D₃) undergoes two further activation steps. It is converted to 25-hydroxycholecalciferol (25-(OH)-D₃) in the liver and further hydroxylated to form calcitriol (1,25-dihydroxycholecalciferol, 1,25-(OH)₂-D₃) in the kidney. This is the most active metabolite and is responsible for much of vitamin D’s activity in the body. Its formation is stimulated both by parathormone, secreted in response to low plasma [Ca²⁺], and by low plasma phosphate concentrations.

Vitamin D acts to elevate plasma levels of both Ca²⁺ and phosphate. It achieves this by:

• increasing the rate of active Ca²⁺ uptake from the gut. This helps replace calcium lost in the urine and is an important mechanism in the maintenance of total body calcium

• stimulating phosphate absorption from the gut

• stimulating Ca²⁺ and phosphate reabsorption in the kidney

• stimulating osteoclastic bone resorption, which releases both Ca²⁺ and phosphate into the extracellular fluid. This effect is only seen with very high levels of activated vitamin D.

Vitamin D also promotes mineralization of newly formed osteoid, which requires Ca²⁺ and phosphate, and adequate supplies are especially important during the periods of rapid skeletal growth in childhood and adolescence.

Calcitonin

This hormone is secreted by the parafollicular C cells of the thyroid gland. It acts on bone to reduce the rate of release of Ca²⁺ to the extracellular fluid and, therefore, tends to lower plasma [Ca²⁺]. It appears to be secreted during episodes of hypercalcaemia (elevated [Ca²⁺]) and may be protective against such abnormal rises. It does not seem to play any significant role in normal Ca²⁺ control.

Regulation of plasma phosphate concentration

The hormones involved in Ca²⁺ control also regulate phosphate, which is present as calcium phosphate in bone mineral and free in solution within the extracellular fluid. Phosphate is also a crucial intracellular ion, acting both as an enzyme cofactor and a substrate for phosphorylation reactions. Parathormone reduces plasma phosphate levels, while calcitriol increases it. Low phosphate concentrations stimulate renal activation of vitamin D and this provides the main feedback system for phosphate control. Increased vitamin D activity will also tend to elevate [Ca²⁺], but this is prevented by the resultant inhibition of parathormone secretion. Under these circumstances, the reduced levels of parathormone make it easier to raise the phosphate concentration since parathormone promotes renal excretion of phosphate.

Box 36 Clinical note: Abnormal Ca²⁺ control

The wide range of causes of low (hypocalcaemia) and high (hypercalcaemia) plasma concentrations of Ca²⁺ will not be considered here. This section will restrict itself to problems resulting from deficient and excess levels of parathormone and vitamin D.

Deficiencies

Hypoparathyroidism may be caused by parathyroid autoantibodies or accidental damage during thyroid surgery. The main outcome is hypocalcaemia with elevated plasma phosphate levels. Increased neuromuscular excitability results and this may lead to muscle tetany, laryngeal spasm and convulsions.

Deficient vitamin D activity may result from an inadequate diet or lipid malabsorption (vitamin D is a fat-soluble vitamin) coupled with low levels of UV exposure. Failure of vitamin D activation may also cause problems in patients with chronic renal failure. There is only likely to be a mild hypocalcaemia, because of the compensatory stimulation of parathormone secretion, but plasma phosphate levels are reduced. The most obvious effects often reflect demineralization of bone, leading to osteomalacia with bone pain in adults and skeletal deformities (rickets) in children.

Excesses

Primary hyperparathyroidism results from failure of the normal negative feedback of plasma [Ca²⁺] on parathormone secretion, often caused by a parathormone-secreting tumour. Plasma [Ca²⁺] is elevated (hypercalcaemia) while phosphate is reduced. Bone destruction causes erosions and cyst formation while calcium may be deposited elsewhere in the body, e.g., in the urine (as renal calculi) and kidneys.

Hypervitaminosis D may result from excessive use of vitamin D supplements. The main effects are those of hypercalcaemia. Plasma phosphate levels will be high.

8.5 Functions of the adrenal cortex

The adrenal glands are situated at the upper poles of each kidney and consist of an outer cortex surrounding the central medulla. These regions are embryologically and functionally distinct and will be considered separately.

Relevant structure and biochemistry

The adrenal cortex secretes a variety of steroid hormones and can be subdivided into three histological zones. The outermost zona glomerulosa is responsible for aldosterone secretion. Beneath it lies the zona fasciculata, while the zona reticularis is immediately adjacent to the medulla. These last two regions are capable of secreting both glucocorticoids (mainly from the zona fasciculata) and adrenal androgens (mainly from the zona reticularis).

Hormone synthesis and excretion

Mitochondrial conversion of cholesterol to pregnenolone provides a common biochemical platform leading to the production of aldosterone (the main mineralocorticoid), cortisol and corticosterone (the main glucocorticoids), and adrenal androgens (Fig. 163). Following release, a considerable fraction of these lipophilic (hydrophobic) adrenal steroids is bound to plasma proteins. Eventually the circulating hormones are broken down in the liver and the metabolites are conjugated with glucuronic acid prior to excretion in the faeces and urine. This explains why conditions associated with excess production of adrenal corticosteroids may be usefully diagnosed by measuring urinary excretion of specific metabolites.